Dideoxypetrosynol A is linear, polyacetylenic target molecule which consist 30 carbon atoms. It’s also C₂-symmetric molecule what is important to planning synthesis, of course. Let’s see structure of dideoxypetrosynol A:

It looks so simple but its spectrum of biological activities is very wide. Dideoxypetrosynol A was isolated from marine sponge (Petrosia sp.) found in Komun islands, Korea. It exhibit anticancer activity aganist ovarian and skin cancer cells. It can also inhibit DNA replication. So, biological properties are interesting but – unfortunately – concentration of dideoxypetrosynol in dry natural source is very poor (just about 23 mg in 14.5 kg dry source). Development of synthesis this target in larger scale is obvious.

There are also some compounds (with interesting biological activity) related to dideoxypetrosynol, for example: duryne 2, petrosynol 3:

Synthesis of such quite simple compounds shouldn’t be very complicated… maybe boring, but in fact – it’s not. Just look at retrosynthesis chart:

Benefits from presence of C₂ symmetry axis are clear. Grignard and Wittig key steps are obvious, but what is the ‘Oxidative coupling of Wittig reagent’? Let’s look at the synthesis to answer this question.

Synthesis starts with 4, TBS-protected terminal alkynol, which is deprotonated by butyllithium in first step and reacted with oxirane in the presence of Me3Al as Lewis acid to give diol 5. Now, free OH group is exchanged to Br and then, by adding triphenylphosphine, phosphonium salt 6 is formed. It’s quite clear. In next step buthyllithium is added again and in next few hours by acting of oxygen from the atmosphere – product 7 is forming. It’s oxidative coupling. Nice reaction.

Next steps are:

and they include deprotection and oxidation to form 8, Wittig olefination to form 9, and Grignard reagent addition to form racemic dideoxypetrosynol 1. Well, racemic.

Finally, racemic product was resolved by enzyme lipase AK:

There are also one feature in this synthesis: why don’t they start their synthesis from 1,4-dichlorobut-2-ene and undergo S_N2 reaction with Grignard reagent derived from corresponding alkyne? Well, actually they wanted to do it in such way but only side products were forming:

For more see:

B. W. Gung, A. O. Omollo, Eur. J. Org. Chem, 2008.

Today, some nice total synthesis – Barrenazines A and B. Structure of these C₂-symmetrical molecules is shown below:

These Barrenazines were isolated in 2003 by Kashman from some (according to authors of article) unidentified tunicates from Barren Islands (Madagascar). They exhibit mild cytotoxic activity against certain tumor cells. The retrosynthetic analysis is shown below:

I can only say that concept of that synthesis is very tricky. I’ve tried predict some step myself utilizing C₂-symmetry of target molecule, but I haven’t thought that central pyrazine ring can be done in such way. Oh, maybe I just have to learn more !

Following retrosynthetic steps are drwan below:

Pyridinium cation ! Nice starting material for that total synthesis ! It’s really interesting that organomagnesium halide addition can be completed to such system. Here, carbonyl group seems to be unreactive.

Synthesis of both (-)-Barrenazine A and B is drawn below:

In first step, to disubstituted pyridine chiral auxiliary was introduced and next completely stereoselective addition of Grignard reagent was undergone. Next, methyl ether was cleavaged to form corresponding ketone. That ketone was undergone reaction with trifluoroacetic acid in chloroform to unprotect tri-i-propylsillyl protecting group. In next step, removal of chiral auxiliary group occured, but later in the same place Boc-protecting group was directed. Next, we have reduction of ketone by using L-selectride reducing agent:

Next, we have free radical azidation in the presence of cerium ammonium nitrate (CAN). Formed in such way azidoketone can dimerize under Staudinger condition. In that step, skeleton of Barrenazines was created. Boc-deprotection gave (-)-Barrenazine B and following hydrogenation gave (-)-Barrenazine A.

For more pieces of informations see:

M. M. Martinez, L. A. Sarandeses, J. P. Sestelo, Tetrahedron Lett., 2007, 48, 8536.

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